Age related macular degeneration (AMD) is a progressive eye condition affecting as many as 10 million Americans. AMD is the number one cause of vision loss and legal blindness in adults over 60 in the U.S. As the population ages, and the “baby boomers” advance into their 60's and 70's, a virtual epidemic of AMD will be prevalent. The disease affects the macula of the eye, where the sharpest central vision occurs. Although it rarely results in complete blindness, it robs the individual of all but the outermost, peripheral vision, leaving only dim images or black holes at the center of vision.
Macular degeneration is categorized as either dry (atrophic) or wet (neovascular). The dry form is more common than the wet, with about 90% of AMD patients diagnosed with dry AMD. The wet form of the disease usually leads to more serious vision loss.
In the dry form, there is a breakdown or thinning of the retinal pigment epithelial cells (RPE) in the macula, hence the term “atrophy”. These RPE cells are important to the function of the retina, as they metabolically support the overlying photoreceptors.
The clinical hallmark of atrophic AMD is accumulation of macular drusen, yellowish deposits just deep to the retinal pigment epithelium (“RPE”). Histopathologic examination of eyes with atrophic AMD reveals deposition of lipid and proteinaceous material deep to the RPE in Bruch's membrane. In aged eyes with AMD, Bruch's membrane is often about 3 times thicker than normal. This thickening is thought to be comprised of lipid as well as modified and cross-linked protein, which impedes transport of nutrients across Bruch's membrane from the choriocapillaris to the outer retina. This thickened barrier comprised of lipid and cross-linked protein impedes transport of nutrients across Bruch's membrane from the choriocapillaris to the outer retina. At present, there is no proven effective treatment for dry AMD other than the use of multivitamins and micronutrients.
Wet AMD occurs when new vessels form and grow through Bruch's membrane into the sub-RPE and subretinal space. This neovascular tissue is very fragile and hyperpermeable. Frequently, it bleeds causing damage to the overlying retina. As the blood organizes, functional macular tissue is replaced by scar tissue. To prevent visual loss, it would be desirable to intervene therapeutically prior to the development of neovascularization.
Although the exact etiology of AMD is not known, several risk factors seem to be important. For example, ARMD may be caused by chronic exposure of the retina to light. The presence or absence of certain nutrients in the diet, such as the antioxidant vitamins E and C, also may affect one's predisposition for ARMD. Other conditions, such as hypertension and smoking, are also considered to be important risk factors for the development of this disease.
AMD is a challenging disease for both patient and doctor, because there are very few treatment options and, with the exception of anti-oxidants, no proven preventative therapy. While some individuals experience only minor inconvenience from macular degeneration, many others with more severe forms of macular degeneration are incapacitated. Current therapies, including laser photocoagulation, photodynamic therapy, and anti-angiogenic therapeutics have had mixed results, and, in certain instances, have caused deleterious side effects. A need therefore exists for a treatment that reduces or limits the effects of macular degeneration.
Laser photocoagulation is effective in clinical trials, but only a minority of patients with AMD are good candidates for treatment. Furthermore, even after successful ablation of choroidal neovascularization with laser treatment recurrent neovascular tissue grows frequently. Visudyne® (Novartis Ophthalmics; Duluth, Ga.), a photodynamic therapy or PDT, uses light-activated drugs to potentially halt or slow abnormal cell growth. The therapy treats late stages of disease, characterized by choroidal neovascularization. Briefly, a photosensitizer is administered intravenously and attaches to lipoprotein receptors, particularly found in cells undergoing rapid proliferation. Shortly after administration, the compound is activated with a pre-calculated dose of light at a particular wavelength, resulting in conversion of normal oxygen to free radical singlet oxygen, which in turn causes closure of neovascular tissue. The therapy, in specific embodiments, treats the blood vessel proliferation. However, because the underlying cause of macular degeneration is not addressed by treatment of choroidal neovascularization with photodynamic therapy, recurrent neovascularization occurs commonly within several months after treatment.
U.S. Pat. No. 5,756,541 is directed to methods to improve visual acuity including administering a photoactive compound in an amount sufficient to localize to a target ocular tissue and irradiating the target tissue with light from a laser, wherein the wavelength of radiation is absorbed by the photoactive compound and the radiation is conducted for a time and at an intensity sufficient to improve visual acuity. In specific embodiments, the photoactive compound is a green porphyrin. U.S. Pat. No. 5,910,510 is directed to an identical method having a particular irradiation timing.
U.S. Pat. No. 5,798,349 regards methods to treat conditions of the eye characterized by unwanted neovasculature, such as AMD, by administering a liposomal formulation of a green porphyrin in an amount and time sufficient to localize in the neovasculature, followed by irradiation of the neovasculature with laser light, wherein the light absorbed by the green porphyrin occludes the neovasculature. In the related U.S. Pat. No. 6,225,303, the irradiance is in a range from about 300 mW/cm2 to about 900 mW/cm2.
U.S. Pat. No. 6,128,525 is directed to method and apparatus controlling dosimetry of photodynamic therapy.
U.S. Pat. No. 5,935,942 regards methods of occluding vasculature in a mammalian eye including co-administering intravenously a fluorescent dye encapsulated with heat-sensitive liposomes and a tissue-reactive agent activated by irradiation. The liposomes are heated in the eye to release their contents, wherein the tissue-reactive agent remains inactive, followed by monitoring of fluorescent dye flow within the vasculature. The tissue-reactive agent is activated in the vasculature having subnormal blood flow, such that the activated agent chemically occludes the vasculature. The related U.S. Pat. No. 6,140,314 methods further comprise coadministration of a tissue-specific factor effective to impair growth or regeneration of a blood vessel. The related U.S. Pat. No. 6,248,727 regards related diagnostic reagents and kits.
Thus, although alternative methods for eye disorders exist, the present invention addresses a need in the art for therapy for the disorder prior to the point of, for example, neovascularization of the eye tissue, particularly in reversing the pathology of a tissue, such as Bruch's membrane, associated with the eye disorder.